2. Academic Validation
  3. STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum

STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum

  • Cell. 2017 Nov 2;171(4):809-823.e13. doi: 10.1016/j.cell.2017.09.034.
Julien Moretti 1,  Soumit Roy 2,  Dominique Bozec 3,  Jennifer Martinez 4,  Jessica R Chapman 5,  Beatrix Ueberheide 5,  Dudley W Lamming 6,  Zhijian J Chen 7,  Tiffany Horng 8,  Garabet Yeretssian 9,  Douglas R Green 10,  J Magarian Blander 11
Affiliations

Affiliations

  • 1 The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
  • 2 Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 3 Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 4 Immunity, Inflammation, and Disease Laboratory, Inflammation and Autoimmunity Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
  • 5 Office of Collaborative Science, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
  • 6 Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
  • 7 Department of Molecular Biology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 8 Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • 9 The Leona M. and Harry B. Helmsley Charitable Trust, New York, NY 10169, USA.
  • 10 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 11 The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA. Electronic address: jmblander@med.cornell.edu.
PMID: 29056340 DOI: 10.1016/j.cell.2017.09.034
Abstract

Constitutive cell-autonomous immunity in metazoans predates interferon-inducible immunity and comprises primordial innate defense. Phagocytes mobilize interferon-inducible responses upon engagement of well-characterized signaling pathways by pathogen-associated molecular patterns (PAMPs). The signals controlling deployment of constitutive cell-autonomous responses during Infection have remained elusive. Vita-PAMPs denote microbial viability, signaling the danger of cellular exploitation by intracellular pathogens. We show that cyclic-di-adenosine monophosphate in live Gram-positive bacteria is a vita-PAMP, engaging the innate sensor stimulator of interferon genes (STING) to mediate endoplasmic reticulum (ER) stress. Subsequent inactivation of the mechanistic target of rapamycin mobilizes Autophagy, which sequesters stressed ER membranes, resolves ER stress, and curtails phagocyte death. This vita-PAMP-induced ER-phagy additionally orchestrates an interferon response by localizing ER-resident STING to autophagosomes. Our findings identify stress-mediated ER-phagy as a cell-autonomous response mobilized by STING-dependent sensing of a specific vita-PAMP and elucidate how innate receptors engage multilayered homeostatic mechanisms to promote immunity and survival after Infection.

Keywords

ER stress; ER-phagy; Gram-positive bacteria; STING; autophagy; c-di-AMP; cell-autonomous innate immunity; mTOR; type-I interferon; vita-PAMP.

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